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Originally published In Press as doi:10.1074/jbc.M209471200 on January 12, 2003

J. Biol. Chem., Vol. 278, Issue 12, 10239-10249, March 21, 2003
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Anti-apoptotic Signaling by the Interleukin-2 Receptor Reveals a Function for Cytoplasmic Tyrosine Residues within the Common gamma  (gamma c) Receptor Subunit*

Matthew J. LindemannDagger , Marta Benczik§, and Sarah L. GaffenDagger §||

From the Dagger  Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263 and the Departments of § Oral Biology and  Microbiology, State University of New York at Buffalo, Buffalo, New York 14214

The interleukin-2 receptor (IL-2R) is composed of one affinity-modulating subunit (IL-2Ralpha ) and two essential signaling subunits (IL-2Rbeta and gamma c). Although most known signaling events are mediated through tyrosine residues located within IL-2Rbeta , no functions have yet been ascribed to gamma c tyrosine residues. In this study, we describe a role for gamma c tyrosines in anti-apoptotic signal transduction. We have shown previously that a tyrosine-deficient IL-2Rbeta chain paired with wild type gamma c stimulated enhancement of bcl-2 mRNA in IL-2-dependent T cells, but it was not determined which region of the IL-2R or which pathway was activated to direct this signaling response. Here we show that up-regulation of Bcl-2 by an IL-2R lacking IL-2Rbeta tyrosine residues leads to increased cell survival after cytokine deprivation; strikingly, this survival signal does not occur in the absence of gamma c tyrosine residues. These gamma c-dependent signals are revealed only in the absence of IL-2Rbeta tyrosines, indicating that the IL-2R engages at least two distinct signaling pathways to regulate apoptosis and Bcl-2 expression. Mechanistically, the gamma c-dependent signal requires activation of Janus kinases 1 and 3 and is sensitive to wortmannin, implicating phosphatidylinositol 3-kinase. Consistent with involvement of phosphatidylinositol 3-kinase, Akt can be activated via tyrosine residues on gamma c. Thus, gamma c mediates an anti-apoptotic signaling pathway through Akt which cooperates with signals from its partner chain, IL-2Rbeta .

* This work was supported by the Departments of Oral Biology and Microbiology at the State University of New York at Buffalo, National Institutes of Health Training Grant DE07034 (to M. J. L.), and Immune Deficiency Foundation and National Institutes of Health Grant AI49329 (to S. L. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

|| To whom correspondence should be addressed: Dept. of Oral Biology, 36 Foster Hall, 3435 Main St., Buffalo, NY 14214. E-mail: sgaffen@buffalo.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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